Pancreatic cancer is the fourth leading cause of cancer death in the United States. The majority of cases are diagnosed late with poor prognosis. Only approximately 20% of the minority of patients that undergo surgical resection with curative intent will survive for five years. There are several different types of unique pancreatic cystic neoplasms and some have malignant potential. They are initially benign lesions, but a mucin-producing subgroup can progress through a series of malignant transformations, leading to the development of adenocarcinoma. Surgical resection is the current standard of care for mucinous cystic neoplasms, but a growing number of pancreatic cysts are being detected by improved diagnostic radiology. In many cases, the etiology of a given cyst and its potential for malignancy remains indeterminate, making it extremely difficult to make recommendations for, or against, a major abdominal surgical intervention (i.e., pancreatic resection). Endoscopic ultrasound with fine needle aspiration is used to obtain cyst fluid to analyze for biomarkers and cytology, but existing biomarkers have limited sensitivity, specificity, predictive values, and accuracy. To our knowledge, proteomic analysis of pancreatic cyst fluid has not been described. We propose to collect cyst fluids from approximately 20 patients to perform a proteomics feasibility study. Our hypothesis is that the protein composition of each individual cyst type contains useful and unique signatures that can be identified by detailed mapping of its proteins, and that these unique signatures will eventually help clinicians to better manage patients with cystic lesions of the pancreas. Specific Aim 1: To characterize the medium molecular weight proteins of the fluids of various cyst types by 2D gel proteomics complemented by a global digestion multidimensional LC/MS/MS proteomics approach. Specific Aim 2: To elicudate the small peptide proteome of the fluids of various cyst types using both MALDI-TOF mass spectrometry and LC/MS/MS mass spectrometry. It is anticipated that this project will provide detailed proteomic definition of the fluids of various types of cystic lesions of the pancreas from which new and more effective biomarkers of malignancy can be selected and validated in future.